11-120862007-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014619.5(GRIK4):c.793A>G(p.Ile265Val) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,613,988 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (23 hom.)
• Consequence: GRIK4 NM_014619.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.10

Genes affected

GRIK4 (HGNC:4582): (glutamate ionotropic receptor kainate type subunit 4) This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068692267).
• BP6: Variant 11-120862007-A-G is Benign according to our data. Variant chr11-120862007-A-G is described in ClinVar as [Benign]. Clinvar id is 768491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00926 (1411/152350) while in subpopulation AFR AF= 0.0316 (1315/41582). AF 95% confidence interval is 0.0302. There are 20 homozygotes in gnomad4. There are 650 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIK4	NM_014619.5	c.793A>G	p.Ile265Val	missense_variant	9/21	ENST00000527524.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK4	ENST00000527524.8	c.793A>G	p.Ile265Val	missense_variant	9/21	2	NM_014619.5	P1

Frequencies

GnomAD3 genomes AF: 0.00926 AC: 1410 AN: 152232 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00231 AC: 581 AN: 251448 Hom.: 4 AF XY: 0.00177 AC XY: 240 AN XY: 135886

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000956 AC: 1398 AN: 1461638 Hom.: 23 Cov.: 30 AF XY: 0.000799 AC XY: 581 AN XY: 727134

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00926 AC: 1411 AN: 152350 Hom.: 20 Cov.: 32 AF XY: 0.00872 AC XY: 650 AN XY: 74512

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00202 Hom.: 4

Bravo AF: 0.0108

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	0.046
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.50	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.075	T;.;T
Sift4G	Benign	0.28	T;.;T
Polyphen		0.0050	B;B;B
Vest4		0.35
MVP		0.69
MPC		0.43
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77196263; hg19: chr11-120732716;